Silicosis is a crippling respiratory disorder characterized by massive lung inflammation and fibrosis. The current study provides evidence on the protective potential of tadalafil; a specific phosphodiesterase-5 (PDE-5) inhibitor against experimentally-induced pulmonary silicosis in rats. Silicosis was induced by intranasal instillation of crystalline silica (50 mg/rat). Halofuginone hydrobromide; a standard collagen-1 synthesis inhibitor was selected as a reference anti-fibrotic. Daily oral administration of tadalafil (1 mg/kg) for 8 weeks significantly ameliorated silica-induced pulmonary damage. BALF content of inflammatory cells, lung total protein, MDA, nitrite/nitrate, tumor necrosis factor α (TNFα), transforming growth factor β1 (TGFβ1) and collagen contents significantly declined with concomitant reduction in serum LDH activity; confirming reduction of silica-induced oxidative stress and inflammation. Meanwhile, lung SOD activity and GSH content significantly increased; confirming restoration of anti-oxidant defenses. Immunohistochemical analysis of lung TGFβ1 expression was correlated with observed biochemical improvements. There was a significant decline in thickness of the walls of the blood vessels and in macrophages and alveolar septal expression of TGFβ1 paralleled with reduction in collagen and extracellular matrix (ECM) components deposition. Ultimately, biochemical and histopathological improvements were accompanied by restoration of normal respiratory functions and reduction in airway hyperactivity and responses to both of carbachol and 5-HT. In conclusion; down-regulation of inflammatory and fibrogenic cytokines expression, restoration of oxidants/antioxidant hemostasis, antioxidant boost and promotion of angiogenesis are implicated in the observed protective effect of tadalafil.